To our knowledge, only one PEGylated drug has been approved for veterinary applications. This is Imrestor, a PEGylated granulocyte colony-stimulating factor, which was approved in 2016 to increase the number of circulating neutrophils in cows and thus prevent breast tissue inflammation .Although PEGylated drugs have been successfully translated to the clinic, a growing body of literature has highlighted the increased presence of PEG-specific antibodies in the general population due to the extensive use of PEG in cosmetic and pharmaceutical products, correlating with the declining therapeutic efficacy of PEGylated active ingredients.This issue is being addressed by the development of alternative polymer-drug conjugates . In the agricultural industry, polymeric seed coatings are used to control pests and diseases that would otherwise inhibit germination and growth.Coating seeds increases their viability, reduces the risk of the active ingredient leaching into the environment, and minimizes off-target toxicity to other organisms compared to free pesticides. More than 180 coating formulations have been reported, including chitosan, polyvinyl acetate , polyvinyl alcohol, PEG, ethyl cellulose, and methyl cellulose.On the market, the majority of seed coating technologies have been developed by Bayer Crop Science, BASF, Corteva, Monsanto, Syngenta, Incotec/Croda, and Germains. Micelles are composed of amphiphilic surfactant molecules that spontaneously aggregate into spherical vesicles in an aqueous environment. This phenomenon is only possible if the quantity of the surfactant molecules is greater than the critical micelle concentration. The core of the micelle is hydrophobic and can sequester hydrophobic active ingredients. The size of the micelle and therefore the amount of active ingredient that can be loaded in its core is dependent on the molecular size, geometry, and polarity of the surfactant.

The small size of polymeric micelles reduces their recognition by scavenging phagocytic and inter-endothelial cells located in the liver and spleen, respectively,garden grow bags and therefore increases the bio-availability of the active ingredient.Most micelles are made of block co-polymers with alternating hydrophilic and hydrophobic segments, and the ratio of drug molecules to the block co-polymers determines their properties. Micelles are often composed of PEG, PLA, PCL, polypropylene oxide, poly-Llysine, or combinations of the above. Estrasorb was approved by the FDA in 2003 as a topical lotion, and consists of micelles designed for the transdermal delivery of 17β-estradiol to the blood for the treatment of menopausal-related vasomotor symptoms. This administration route evades first-pass metabolism, achieving stable levels of 17β-estradiol in the serum for 14 days. Furthermore, paclitaxel and docetaxel are commercially available formulated as micellar nanocarriers, thus avoiding the use of Kolliphor EL as a solvent.Various micellar nanocarriers are currently undergoing clinical trials . For example, NK012 is a micellar polyglutamate-PEG formulation covalently bound to the antineoplastic topoisomerase inhibitor SN-38 via an ester bond. SN-38 is slowly released from NK012 by the hydrolysis of the ester bond under physiological conditions, which increases the SN-38 half-life to 210 h. NK012 is undergoing clinical trials for the treatment of solid tumors, triple-negative breast cancer, colorectal cancer, and small-cell lung cancer.Similarly, the NK105 micelle is being investigated for the delivery of paclitaxel to breast cancer, gastric cancer, and non-small-cell lung cancer. NK105 polymers consist of PEG as the hydrophilic segment and modified polyaspartate as the hydrophobic segment.Genexol-PM is a micellar nanocarrier consisting of mPEG-block-D,L-PLA for the delivery of paclitaxel for the treatment of non-small-cell lung cancer, hepatocellular carcinoma, urothelial cancer, ovarian cancer, and pancreatic cancer.

Genexol-PM was shown to behave similarly to the FDA/EMA-approved nanocarrier Abraxane and has been approved for the treatment of metastatic breast cancer and advanced non-small-cell lung cancer in South Korea. NC-6004 is being investigated for the delivery of cisplatin to head and neck cancer as well as non-small-cell lung cancer. NC-6004 demonstrated a significant reduction in cisplatin-induced neurotoxicity and nephrotoxicity . Micelles are also being investigated for the treatment of cystic fibrosis, metabolic syndrome, psoriasis, and rheumatoid arthritis.In veterinary medicine, a randomized trial was initiated in 2013 to investigate the safety and efficacy of micellar paclitaxel for the treatment of dogs with grade II or III mast cell tumors .The micelle consisted of a surfactant derivative of retinoic acid . Dogs treated with micellar paclitaxel showed a three-fold higher treatment response compared to a control group receiving the standard-of-care drug lomustine. However, the FDA conditional approval of Paccal Vet-CA1 was withdrawn in 2017 by the manufacturer Oasmia Pharmaceutical AB to allow them time to study lower doses in order to reduce adverse effects such as neutropenia, hepatopathy, anorexia, and diarrhea. In a different application, a micellar vitamin E has been tested as an antioxidant in race horses undergoing prolonged aerobic exercise to prevent exercise-induced oxidative lesions, and maintained the general oxidative status to a healthy level for horses undergoing intensive training.Micelles have also been developed as promising nanocarriers for the encapsulation of pesticides, helping to prevent adsorption to soil particles. Examples include the micellar encapsulation of azadirachtin,carbendazim,carbofuran,imidacloprid,rotenone,thiamethoxam,and thiram.These formulations are still undergoing development and have been tested in vitro and in the field. Inorganic nanocarriers include natural and synthetic materials based on silica, clay, and metals such as silver, gold, titanium, iron, copper, and zinc. These nanocarriers are physiologically compatible, resistant to microbial degradation, and environmentally friendly, which makes them suitable for medical, veterinary, and agricultural applications. Even so, their use as nanocarriers has been somewhat overshadowed by their success in other medical applications.

In particular, metallic nanoparticles have been developed as theranostic and photothermal reagents, and for the treatment of iron deficiency. The first formulation approved by the FDA in 1974 was iron dextran for the treatment of iron deficiency. Eight more formulations have since been approved by the FDA or EMA . We do not consider these formulations as nanocarriers because the treatment modalities rely entirely on the nanoparticle itself without a cargo of active ingredients. However, metallic nanocarriers have recently been proposed in which the active ingredient is attached to the surface by physical absorption, electrostatic interactions, or conjugation.In particular, gold nanoparticles allow the conjugation of many biological ligands, including DNA and siRNA.Thus far, only one clinical trial has been carried out using metallic nanocarriers, namely spherical nucleic acid gold nanoparticles for the delivery of siRNA to patients with glioblastoma or gliosarcoma . More advanced metallic nanocarriers are under development, including particles that can respond to external triggers, such as light, magnetic fields, and hyperthermia to release their cargo in a controlled manner. For example, gold and silver nanoparticles have been conjugated to various cancer drugs.Mesoporous silica nanocarriers have been investigated extensively because they are stable particles with a high payload capacity due their porous structure, they have a tunable pore diameter , and surface modifications can impart new functionalities such as targeted delivery.MSNs have already been tested in the laboratory to deliver cancer drugs such as doxorubicin and camptothecin, antibiotics such as erythromycin and vancomycin, and anti-inflammatories such as ibuprofen and naproxen,tomato grow bag with remarkably high loading rates of up to 600 milligrams of cargo per gram of silica.This loading capacity of up to 60% far exceeds that of liposomal and polymeric nanocarriers. For example, the liposomal formulation Doxil and the polymeric formulation Eligard achieve loading capacities of 31% and 27%, respectively. However, some silica nanoparticle formulations have been shown to cause hemolysis due to strong interactions between silanol groups on the carrier and phospholipids in the erythrocyte plasma membrane.Another concern is their persistence in vivo due to the absence of renal clearance. These issues could be addressed by modifying the surface chemistry or applying coatings. In an agricultural context, silica is already highly abundant in soil and such particles could therefore be engineered for the controlled release of active ingredients without the carrier itself causing environmental harm. For example, MSNs have been used to deliver the insecticide chlorfenapyr over a period of 20 weeks, which doubled the insecticidal activity in field tests.The fungicide metalaxyl was also loaded into MSNs, allowing its slow release in soil and water for a period of 30 days.Similarly, nanocarriers based on naturally occurring aluminum silicates have been formed into phyllosilicate sheets for the intercalation of antibiotics and herbicides, allowing sustained delivery.Several metallic nanoparticles have demonstrated antimicrobial properties, and the EPA has already approved silver nanoparticles for use as an antimicrobial agent in clothing, but not yet for the delivery of active ingredients. Finally, carbon nanotubes are also being investigated for medical and agricultural uses because their shape and surface chemistry confer unique properties, although their toxicity remains a translational barrier. I recommend the following reviews for further information. Over the course of evolution, nature has yielded a variety of bio-materials with great structural complexity that remains difficult to emulate.

The analysis of such complexity requires the appropriate molecular methods, and for this reason the development of proteinaceous nanocarriers has lagged behind that of the simpler liposomal, polymeric, and micellar structures.The production of proteinaceous nanocarriers has also required the development of tools for the expression of recombinant proteins and strategies for creation or diversity, such as directed evolution, genome editing and synthetic biology. These tools have allowed the production of hierarchically organized proteinaceous structures, including albumin nanoparticles, heat shock protein cages, vault proteins, and ferritins.These comprise repeated protein sub-units forming highly organized nanostructures that are identical in size and chemical composition. Although synthetic nanoparticles can also be assembled into complex structures, the sophistication and monodispersity that can be achieved with proteins has yet to be replicated. Proteinaceous nanoparticles have been used as biocatalysts for the synthesis of novel materials, but are also useful for the delivery of active ingredients in medicine and agriculture.The first proteinaceous nanocarriers were developed to mimic the properties of plasma proteins, thus increasing circulation times and reducing systemic side effects. In 2005, the FDA approved the proteinaceous nanoshell Abraxane, consisting of albumin-bound paclitaxel for the treatment of breast cancer. The conjugation of paclitaxel to albumin stabilized the drug even in the absence of Kolliphor EL, and enhanced the uptake of the active ingredient compared to the Kolliphor EL formulation.Given the safety and efficacy of drugs conjugated to albumin, two other albumin nanocarriers are undergoing clinical trials . The first is an albumin conjugate of the protein kinase inhibitor rapamycin indicated for colorectal cancer, bladder cancer, glioblastoma, sarcoma, and myeloma.The second is an albumin conjugate of docetaxel indicated for the treatment of prostate cancer. Albumin has a long circulation half-life due to its interaction with the recycling Fc receptor. It is beneficial for the delivery of small molecules that are unstable or have low solubility in blood, as well as proteins and peptides that are rapidly cleared from the circulation. Small molecules can be chemically fused to albumin and administered as conjugate, and strategies to target small-molecule drug cargoes to albumin in vivo have also been developed.Heat shock protein cages, vault proteins, and ferritins have also been investigated for the delivery of active ingredients, although no clinical trials have been reported thus far. Heat shock proteins are chaperones that promote the folding of newly synthesized proteins and the refolding of denatured ones, which means they are naturally stable and possess channels and cavities for the sequestration of cargo.There are five families of heat shock proteins: Hsp100, Hsp90, Hsp70, and Hsp60 , and the small heat shock protein family, ranging in size from 12 to 43 kDa. Heat shock proteins assemble into large complexes that vary in size and shape , and they can be engineered to carry and deliver active ingredients such as doxorubicin.Vault nanoparticles are barrel-like ribonucleoproteins found in many eukaryotes. They are 41 x 73 nm in size and resemble the vault of a gothic cathedral. Their precise biological function remains unknown, although they are thought to play a role in nuclear transport, immunity and defense against toxins.Several proteins have been encapsulated in vault nanocarriers, including the lymphoid chemokines CCL19 and CCL21, the New York esophageal squamous cell carcinoma 1 antigen, the precursor of adenovirus protein VI , the major outer membrane protein of Chlamydia trachomatis, and the egg storage protein ovalbumin.Vault Pharma is one company specializing in the development of these structures. Finally, ferritin is an iron-storage protein with 24 subunits that self-assemble into a spherical cage structure 12 nm in diameter with a molecular mass of 450 kDa.